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| *[[warfarin]]. | | *[[warfarin]]. |
| These agents are also sometimes referred to as [[antithrombin]]s, although, it should be noted that they often inhibit one or more proteins in the coagulation cascade before [[thrombin]]. | | These agents are also sometimes referred to as [[antithrombin]]s, although, it should be noted that they often inhibit one or more proteins in the coagulation cascade before [[thrombin]]. |
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| ==Unfractionated Heparin(UFH)==
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| '''Mechanism of action:'''
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| *[[Unfractionated heparin]] exerts its anticoagulant effect by potentiating the action of circulating [[antithrombin]], a proteolytic enzyme that inactivates factor IIa ([[thrombin]]), factor IXa, and factor Xa.
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| *It prevents thrombus propagation but does not lyse existing thrombi.
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| '''Clinical trial data:'''
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| *A meta-analysis showed that in [[aspirin]]-treated patients with [[acute coronary syndrome]] without ST elevation, short-term [[unfractionated heparin]] or [[LMWH]] halves the risk of [[myocardial infarction]] or death<ref name="pmid10859038">{{cite journal | author = Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S | title = Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis | journal = [[Lancet]] | volume = 355 | issue = 9219 | pages = 1936–42 | year = 2000 | month = June | pmid = 10859038 | doi = 10.1016/S0140-6736(00)02324-2 | url = http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(00)02324-2 | accessdate = 2011-04-11}}</ref>.
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| '''Dosing:'''
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| *This is a short acting drug with an anticoagulation half life of 1.5hrs. Hence, frequent monitoring of the anticoagulant response using [[activated partial thromboplastin time]] (APTT) is recommended with titrations made according to a standardized nomogram aiming for an APTT range between 1.5 to 2 times control or 50 to 70 seconds .
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| '''Adverse effects:'''
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| *bleeding(specially with elevated [[APTT]])
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| *[[heparin induced thrombocytopenia]]
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| ==Low Molecular Weight Heparin(LMWH)==
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| '''Mechanism of benefit:'''
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| *[[LMWH]] combine factor IIa and factor Xa inhibition and thus inhibit both the action and generation of thrombin.
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| *It has a number of advantages over [[UFH]] such as its greater anti-factor Xa activity inhibits thrombin generation more effectively, lower rate of [[thrombocytopenia]], high bioavailabiltiy, more consistent anticoagulant effect and no requirement of intensive lab monitoring.
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| '''Clinical trial data:'''
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| *Results from TIMI 11B study<ref name="pmid10517729">{{cite journal |author=Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D, Bayes De Luna A, Fox K, Lablanche JM, Radley D, Premmereur J, Braunwald E |title=Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial |journal=[[Circulation]] |volume=100 |issue=15 |pages=1593–601 |year=1999 |month=October |pmid=10517729 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=10517729 |accessdate=2011-04-11}}</ref> showed superiority of [[LMWH]] over [[UFH]] for reducing a composite of death and serious cardiac ischemic events during the acute management of [[Unstable angina]]/NQMI patients without causing a significant increase in the rate of major [[hemorrhage]].
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| *Results from SYNERGY trial<ref name="pmid15238590">{{cite journal |author=Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW, Avezum A, Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, Gulba DC, Guneri S, Gurfinkel E, Harrington R, Hochman JS, Kleiman NS, Leon MB, Lopez-Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, Toro-Figueroa L, White H |title=Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=292 |issue=1 |pages=45–54 |year=2004 |month=July |pmid=15238590 |doi=10.1001/jama.292.1.45 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15238590 |accessdate=2011-04-11}}</ref> revealed noninferiority of [[LMWH]] over [[UFH]] for the treatment of high-risk patients with non-ST-segment elevation [[ACS]]. However, both trials did show increased risk of major bleeding with [[LMWH]].
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| *A prospective analysis of the A to Z trial<ref name="pmid15451146">{{cite journal |author=de Lemos JA, Blazing MA, Wiviott SD, Brady WE, White HD, Fox KA, Palmisano J, Ramsey KE, Bilheimer DW, Lewis EF, Pfeffer M, Califf RM, Braunwald E |title=Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial |journal=[[European Heart Journal]] |volume=25 |issue=19 |pages=1688–94 |year=2004 |month=October |pmid=15451146 |doi=10.1016/j.ehj.2004.06.028 |url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15451146 |accessdate=2011-04-11}}</ref> showed that [[enoxaparin]] provided significant benefit over [[UFH]] in patients managed conservatively (who are typically on [[heparin]]/[[LMWH]] for at least 48 hours) but not in those with early invasive approach(who are taken to the catheterization laboratory within 48 hours and have their [[heparin]] discontinued thereafter).
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| '''Disadvantages of LMWH:'''
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| *[[LMWH]] are more affected by renal dysfunction than [[UFH]], and the dose should be reduced in patients with a creatinine clearance <30 mL/min.
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| *Also, in the event of bleeding, the anticoagulant effect of [[UFH]] can be reversed more effectively with [[protamine]].
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| ==Direct Thrombin Inhibitors==
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| [[Hirudin]] which is the prototype of this class of drugs has been studied in multiple trials with mixed results. Other drugs in this class include [[bivalirudin]], [[argatroban]], efegatran and inogatran. [[Bivalirudin]] is a synthetic analog of [[hirudin]] that binds reversibly to [[thrombin]] and inhibits clot-bound thrombin.
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| '''Indications:'''
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| *Hirudin (lepirudin) is presently indicated by the US Food and Drug Administration only for anticoagulation in patients with [[heparin-induced thrombocytopenia]] and for the prophylaxis of [[deep vein thrombosis]] in patients undergoing hip replacement surgery.
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| *[[Argatroban]] is another direct thrombin inhibitor that is approved for the management of patients with [[heparin-induced thrombocytopenia]].
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| '''Clinical trial data:'''
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| *The relative benefits of [[hirudin]] versus [[UFH]] in [[ACS]] patients was evaluated in the 12,142 patient in GUSTO-IIb trial<ref name="pmid8778585">{{cite journal |author= |title=A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators |journal=[[The New England Journal of Medicine]] |volume=335 |issue=11 |pages=775–82 |year=1996 |month=September |pmid=8778585 |doi=10.1056/NEJM199609123351103 |url=http://dx.doi.org/10.1056/NEJM199609123351103 |accessdate=2011-04-11}}</ref>. A reduction in risk for nonfatal [[MI]] was seen without increased risk of major bleeding.
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| *TIMI 9B study failed to show any difference in outcomes in [[Hirudin]] verus [[heparin]] treated patients getting [[TPA]].
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| *The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial<ref name="pmid17124018">{{cite journal |author=Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM |title=Bivalirudin for patients with acute coronary syndromes |journal=[[The New England Journal of Medicine]] |volume=355 |issue=21 |pages=2203–16 |year=2006 |month=November |pmid=17124018 |doi=10.1056/NEJMoa062437 |url=http://dx.doi.org/10.1056/NEJMoa062437 |accessdate=2011-04-11}}</ref> randomized 13,819 patients with [[Unstable angina]]/[[NSTEMI]] to one of three treatments: [[UFH]], or [[enoxaparin]] plus a [[GP IIb/IIIa inhibitor]], or [[bivalirudin]] plus a [[GP IIb/IIIa inhibitor]], or [[bivalirudin]] alone. Patients were managed with an early invasive strategy and the primary endpoint was the composite of death, [[myocardial infarction]], unplanned revascularization for [[ischemia]], and major bleeding at 30 days. No differences were observed in the direct comparison of the anticoagulants i.e., between bivalirudin plus GP IIb/IIIa inhibitor and UFH/enoxaparin plus a GP IIb/IIIa inhibitor or bivalirudin alone. But for the bivalirudin alone group, when compared with the group receiving UFH/enoxaparin plus a GP IIb/IIIa inhibitor, there was decrease risk for bleeding.
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| '''Disadvantage of Direct Thrombin Inhibitors:'''
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| *Direct thrombin inhibitors lack a protamine-binding domain, hence it is not possible to reverse the effect with [[protamine]]. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., [[fresh frozen plasma]])is required.
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| *In [[ACS]], the monovalent direct thrombin inhibitors(including argatroban) are ineffective anti-thrombotic agents compared with [[UFH]], and thus, [[argatroban]] should generally not be used in management of [[ACS]].
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| ==Factor Xa Inhibitors==
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| [[Fondaparinux]] is the prototype in this class of drug which is an indirect Xa inhibitor that requires antithrombin for its action.
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| '''Clinical trial data:'''
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| *The OASIS 5 and 6 trials<ref name="pmid18955665">{{cite journal |author=Mehta SR, Boden WE, Eikelboom JW, Flather M, Steg PG, Avezum A, Afzal R, Piegas LS, Faxon DP, Widimsky P, Budaj A, Chrolavicius S, Rupprecht HJ, Jolly S, Granger CB, Fox KA, Bassand JP, Yusuf S |title=Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials |journal=[[Circulation]] |volume=118 |issue=20 |pages=2038–46 |year=2008 |month=November |pmid=18955665 |doi=10.1161/CIRCULATIONAHA.108.789479 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18955665 |accessdate=2011-04-11}}</ref> evaluated the use of [[fondaparinux]] in [[ACS]] and compared it with a [[heparin]]-based strategy. Results showed that compared to heparin based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of [[acute coronary syndromes]] and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.
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| *The OASIS-5 trial<ref name="pmid17964037">{{cite journal |author=Mehta SR, Granger CB, Eikelboom JW, Bassand JP, Wallentin L, Faxon DP, Peters RJ, Budaj A, Afzal R, Chrolavicius S, Fox KA, Yusuf S |title=Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial |journal=[[Journal of the American College of Cardiology]] |volume=50 |issue=18 |pages=1742–51 |year=2007 |month=October |pmid=17964037 |doi=10.1016/j.jacc.2007.07.042 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(07)02494-1 |accessdate=2011-04-11}}</ref> specifically compared [[fondaparinux]], administered at a relatively low dose, 2.5 mg subcutaneously, once daily with standard-dose [[enoxaparin]] in 20,078 patients with high-risk [[UA]]/[[NSTEMI]]. The rates of death, [[MI]], or refractory [[ischemia]] throughout the first 9 days were similar with [[fondaparinux]] and [[enoxaparin]]. Of note, however, the rate of major bleeding was almost 50 percent lower in the fondaparinux arm. By 30 days, mortality was significantly lower in the fondaparinux arm. However, in the subset of patients undergoing [[PCI]], fondaparinux was associated with more than a threefold increased risk of catheter-related thrombi.
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| '''Disadvantage of Factor Xa Inhibitors:'''
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| *[[fondaparinux]] lacks a protamine-binding domain, hence it is not possible to reverse the effect with [[protamine]]. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., [[fresh-frozen plasma]])is required.
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| ==Long Term Anticoagulation==
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| [[Warfarin]] is the typical drug used for long term anticoagulation. However, its role, if any, in patients with [[UA]]/[[NSTEMI]] has not been clearly defined.
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| '''Clinical trial data:'''
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| *ASPECT 2 trial<ref name="pmid12126819">{{cite journal |author=van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE |title=Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial |journal=Lancet |volume=360 |issue=9327 |pages=109–13 |year=2002 |month=July |pmid=12126819 |doi=10.1016/S0140-6736(02)09409-6 |url=}}</ref> showed that in patients recently admitted with [[ACS]], treatment with high-intensity oral anticoagulants or [[aspirin]] with medium-intensity oral anticoagulants was more effective than aspirin alone in reduction of subsequent cardiovascular events and death. However, similar benefit is seen with [[clopidogrel]] plus aspirin over aspirin alone, the lack of need for monitoring of the [[INR]], and the frequent use of [[PCI]] and stenting in the patient population in whom the need for clopidogrel is well established, the clinical use of aspirin plus warfarin is limited. Among patients without a coronary stent but with another indication for warfarin, such as chronic [[atrial fibrillation]], mechanical valve or severe [[left ventricular dysfunction]] who are at high risk of systemic [[embolization]], the combination of aspirin plus warfarin would be preferable as the long-term antithrombotic strategy.
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| ==ACC / AHA Guidelines for Anticoagulation Therapy (DO NOT EDIT)==
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| {{cquote|
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| ===Class I===
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| # Anticoagulant therapy should be added to [[antiplatelet therapy]] in [[UA]] / [[NSTEMI]] patients as soon as possible after presentation.
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| ::a. For patients in whom an invasive strategy is selected, regimens with established efficacy at a ''Level of Evidence: A'' include [[enoxaparin]] and [[UFH]], and those with established efficacy at a ''Level of Evidence: B'' include [[bivalirudin]] and [[fondaparinux]].
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| ::b. For patients in whom a conservative strategy is selected, regimens using either [[enoxaparin]] or [[UFH]] (Level of Evidence: A) or [[fondaparinux]] (Level of Evidence: B) have established efficacy.
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| ::c. In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, [[fondaparinux]] is preferable. (Level of Evidence: B)
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| ===Class IIa===
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| # For [[UA]] / [[NSTEMI]] patients in whom an initial conservative strategy is selected, [[enoxaparin]] or [[fondaparinux]] is preferable to [[UFH]] as [[anticoagulant therapy]], unless [[CABG]] is planned within 24 h. (Level of Evidence: B)}}
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| ==See Also== | | ==See Also== |